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Yu ZW, Zheng M, Fan HY, Liang XH, Tang YL. Ultraviolet (UV) radiation: a double-edged sword in cancer development and therapy. MOLECULAR BIOMEDICINE 2024; 5:49. [PMID: 39417901 PMCID: PMC11486887 DOI: 10.1186/s43556-024-00209-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
It has long been widely acknowledged that ultraviolet (UV) light is an environment risk factor that can lead to cancer, particularly skin cancer. However, it is worth noting that UV radiation holds potential for cancer treatment as a relatively high-energy electromagnetic wave. With the help of nanomaterials, the role of UV radiation has caught increasing attention in cancer treatment. In this review, we briefly summarized types of UV-induced cancers, including malignant melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma. Importantly, we discussed the primary mechanisms underlying UV carcinogenesis, including mutations by DNA damage, immunosuppression, inflammation and epigenetic alterations. Historically limited by its shallow penetration depth, the introduction of nanomaterials has dramatically transformed the utilization of UV light in cancer treatment. The direct effect of UV light itself generally leads to the suppression of cancer cell growth and the initiation of apoptosis and ferroptosis. It can also be utilized to activate photosensitizers for reactive oxygen species (ROS) production, sensitize radiotherapy and achieve controlled drug release. Finally, we comprehensively weigh the significant risks and limitations associated with the therapeutic use of UV radiation. And the contradictory effect of UV exposure in promoting and inhibiting tumor has been discussed. This review provides clues for potential clinical therapy as well as future study directions in the UV radiation field. The precise delivery and control of UV light or nanomaterials and the wavelength as well as dose effects of UV light are needed for a thorough understanding of UV radiation.
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Affiliation(s)
- Zhen-Wei Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Min Zheng
- Department of Stomatology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Hua-Yang Fan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China.
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Ocanha-Xavier JP, Xavier-Junior JCC, Miot HA, da Silva MG, Marques MEA. Transcriptomic analysis of genes associated with vitamin D receptor signalling reveals differences between skin cancers. Exp Dermatol 2024; 33:e15160. [PMID: 39435723 DOI: 10.1111/exd.15160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 07/10/2024] [Accepted: 08/05/2024] [Indexed: 10/23/2024]
Abstract
Vitamin D activates the vitamin D receptor (VDR), which dimerizes preferentially with the retinoid X receptor-α (RXRα). This heterodimer connects with genetic elements responsive to vitamin D, inhibiting or stimulating gene activity. We performed Nanostring® analysis of VDR/RXRα to compare the mRNA expression of this heterodimer and their correlated transcriptomes in non-melanoma skin cancer (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) and melanocytic lesions (intradermal nevi (IN), and melanomas (MM)) with control skin. To evaluate VDR, RXRα and other 22 correlated genes in BCC, SCC, IN and MM, paraffin samples had their transcriptomes analysed using Nanostring®, a platform that allows multiple mRNA analyses. There were 46 samples, including 11 BCC, 10 SCC, 10 IN, 12 MM and 3 pools of control skins. Most mRNAs differed between the lesion groups and the control group. BCC and SCC NCOR2 were upregulated; in MM and IN, RXRγ was higher than in the control group. TP53, FOXO3 and MED1 showed a significant difference when we compared the BCC group to the SCC group. Melanoma and intradermal nevi differed only in AhR. VDR and RXRα were lower than the control in all groups. The panel shows a clear difference between the non-melanocytic cancers and, on the other hand, a slight difference between the melanocytic lesions. The study of vitamin D's influence through its receptor and RXRα is an exciting issue for understanding the importance of this pathway, and the present study can impact the prevention and treatment strategies, mainly in non-melanocytic tumours.
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Affiliation(s)
- Juliana Polizel Ocanha-Xavier
- Department of Pathology, São Paulo State University-UNESP, Botucatu, São Paulo, Brazil
- Private Clinic (JPOX Clinic), Araçatuba, São Paulo, Brazil
| | - José Cândido Caldeira Xavier-Junior
- Department of Pathology, São Paulo State University-UNESP, Botucatu, São Paulo, Brazil
- Araçatuba Institute of Pathology, Araçatuba, São Paulo, Brazil
- Salesian Catholic University Center Auxilium (UNISALESIANO), Medical School, Araçatuba, São Paulo, Brazil
| | - Hélio Amante Miot
- Department of Dermatology, São Paulo State University-UNESP, Botucatu, São Paulo, Brazil
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Chen S, Chen H, Wang X, Zhang D, Zhang L, Cheng J, Zhang Q, Hua Z, Miao X, Shi J. Expression analysis and biological regulation of silencing regulatory protein 6 (SIRT6) in cutaneous squamous cell carcinoma. An Bras Dermatol 2024; 99:535-545. [PMID: 38548549 PMCID: PMC11220918 DOI: 10.1016/j.abd.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer worldwide. Therefore, the identification of biomarkers associated with CSCC progression could aid in the early detection of high-risk squamous cell carcinoma and the development of novel therapeutic strategies. OBJECTIVE This study aimed to investigate the expression patterns of silent mating type Information Regulation 2 homolog 6 (SIRT6) in CSCC and its clinical significance. METHODS The protein expression level of SIRT6 in tissues was detected by immunohistochemistry, and the correlation between SIRT6 expression and clinicopathological parameters in CSCC patients was analyzed. The relative expression of SIRT6 in CSCC cell lineage and tissue specimens was determined by western blotting and PCR. The effect of SIRT6 silencing on cell proliferation was evaluated using cell counting kit 8. Wound healing, transwell method, and flow cytometry were used to investigate the migration, invasion, and cell cycle distribution/apoptosis of CSCC cells after SIRT6 silencing, respectively. Western blot was used to detect the expression of EMT (Epithelial-Mesenchymal Transition), cycle, apoptosis, and other related proteins. RESULTS The high expression of SIRT6 was correlated with the location of cancer tissue and Broder staging in CSCC patients. Knockdown of SIRT6 inhibited the proliferation, migration, invasion and EMT of CSCC cells, and promoted their apoptosis, with cells blocked in G1 phase. STUDY LIMITATIONS No animal experiments were conducted to further verify the results. CONCLUSION Decreased expression of SIRT6 can inhibit the occurrence and development of CSCC.
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Affiliation(s)
- Sai Chen
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Hongxia Chen
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Xu Wang
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Dongmei Zhang
- Jiangsu Provincial Medical Key Discipline (Laboratory) Cultivation Unit of Immunology, Nantong First People's Hospital, People's Republic of China; Medical Research Center, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Li Zhang
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Jiawei Cheng
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Qi Zhang
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Zhixiang Hua
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Xu Miao
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China
| | - Jian Shi
- Department of Dermatology, Affiliated Hospital 2 of Nantong University, People's Republic of China.
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Liang X, Zhang C, Shen L, Ding L, Guo H. Role of non‑coding RNAs in UV‑induced radiation effects (Review). Exp Ther Med 2024; 27:262. [PMID: 38756908 PMCID: PMC11097301 DOI: 10.3892/etm.2024.12550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/04/2024] [Indexed: 05/18/2024] Open
Abstract
Ultraviolet (UV) is divided into UVA (long-wave, 320-400 nm), UVB (middle-wave, 280-320 nm) and UVC (short-wave, 100-280 nm) based on wavelength. UV radiation (UVR) from sunlight (UVA + UVB) is a major cause of skin photodamage including skin inflammation, aging and pigmentation. Accidental exposure to UVC burns the skin and induces skin cancer. In addition to the skin, UV radiation can also impair visual function. Non-coding RNAs (ncRNAs) are a class of functional RNAs that do not have coding activity but can control cellular processes at the post-transcriptional level, including microRNA (miRNA), long non-coding RNA (lncRNA) and circulatory RNA (circRNA). Through a review of the literature, it was determined that UVR can affect the expression of various ncRNAs, and that this regulation may be wavelength specific. Functionally, ncRNAs participate in the regulation of photodamage through various pathways and play pathogenic or protective regulatory roles. In addition, ncRNAs that are upregulated or downregulated by UVR can serve as biomarkers for UV-induced diseases, aiding in diagnosis and prognosis assessment. Therapeutic strategies targeting ncRNAs, including the use of natural drugs and their extracts, have shown protective effects against UV-induced photodamage. In the present review, an extensive summarization of previous studies was performed and the role and mechanism of ncRNAs in UV-induced radiation effects was reviewed to aid in the diagnosis and treatment of UV-related diseases.
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Affiliation(s)
- Xiaofei Liang
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Chao Zhang
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Lijuan Shen
- Department of Laboratory Medicine, Qiqihar MingZhu Hospital, Qiqihar, Heilongjiang 161000, P.R. China
| | - Ling Ding
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Haipeng Guo
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
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Bender M, Chen IP, Henning S, Degenhardt S, Mhamdi-Ghodbani M, Starzonek C, Volkmer B, Greinert R. Knockdown of Simulated-Solar-Radiation-Sensitive miR-205-5p Does Not Induce Progression of Cutaneous Squamous Cell Carcinoma In Vitro. Int J Mol Sci 2023; 24:16428. [PMID: 38003618 PMCID: PMC10671527 DOI: 10.3390/ijms242216428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Solar radiation is the main risk factor for cSCC development, yet it is unclear whether the progression of cSCC is promoted by solar radiation in the same way as initial tumorigenesis. Additionally, the role of miRNAs, which exert crucial functions in various tumors, needs to be further elucidated in the context of cSCC progression and connection to solar radiation. Thus, we chronically irradiated five cSCC cell lines (Met-1, Met-4, SCC-12, SCC-13, SCL-II) with a custom-built irradiation device mimicking the solar spectrum (UVB, UVA, visible light (VIS), and near-infrared (IRA)). Subsequently, miRNA expression of 51 cancer-associated miRNAs was scrutinized using a flow cytometric multiplex quantification assay (FirePlex®, Abcam). In total, nine miRNAs were differentially expressed in cell-type-specific as well as universal manners. miR-205-5p was the only miRNA downregulated after SSR-irradiation in agreement with previously gathered data in tissue samples. However, inhibition of miR-205-5p with an antagomir did not affect cell cycle, cell growth, apoptosis, or migration in vitro despite transient upregulation of oncogenic target genes after miR-205-5p knockdown. These results render miR-205-5p an unlikely intracellular effector in cSCC progression. Thus, effects on intercellular communication in cSCC or the simultaneous examination of complementary miRNA sets should be investigated.
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Affiliation(s)
| | | | | | | | | | | | | | - Rüdiger Greinert
- Skin Cancer Center, Division of Molecular Cell Biology, Elbe Kliniken Stade-Buxtehude, 21614 Buxtehude, Germany; (M.B.); (I.-P.C.); (S.H.); (M.M.-G.); (C.S.); (B.V.)
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Zhao J, Zhang X, Zhang D, Tang Q, Bi Y, Yuan L, Yang B, Li X, Li Z, Deng D, Cao W. Critical genes in human photoaged skin identified using weighted gene co-expression network analysis. Genomics 2023; 115:110682. [PMID: 37454939 DOI: 10.1016/j.ygeno.2023.110682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 05/24/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023]
Abstract
Photoaging is unique to the skin and is accompanied by an increased risk of tumors. To explore the transcriptomic regulatory mechanism of skin photoaging, the epidermis, and dermis of 16 healthy donors (eight exposed and eight non-exposed) were surgically excised and detected using total RNA-Seq. Weighted gene co-expression network analysis (WGCNA) identified the most relevant modules with exposure. The hub genes were identified using correlation, p-value, and enrichment analysis. The critical genes were identified using Support Vector Machine-Recursive Feature Elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression, then enriched using single-gene GSEA. A competitive endogenous RNA (ceRNA) network was constructed and validated using qRT-PCR. Compared with non-exposed sites, 430 mRNAs, 168 lncRNAs, and 136 miRNAs were differentially expressed in the exposed skin. WGCNA identified the module MEthistle and 12 intersecting genes from the 71 genes in this module. The enriched pathways were related to muscle. The critical genes were KLHL41, MYBPC2, and ERAP2. Single-gene GSEA identified the Hippo signaling pathway, basal cell carcinoma, cell adhesion molecules, and other pathways. Six miRNAs and 18 lncRNAs related to the critical genes constituted the ceRNA network and were verified using qPCR. The differential expression of KLHL41, MYBPC2, and ERAP2 at the protein level was verified using immunohistochemistry. KLHL41, MYBPC2, and ERAP2 genes are related to skin photoaging. The prediction model based on the three critical genes can indicate photoaging. These critical genes may have a role in skin photoaging by regulating cell growth, intercellular adhesion, and substance metabolism pathways.
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Affiliation(s)
- Jie Zhao
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xun Zhang
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Dafu Zhang
- Department of Radiology, Yunnan Cancer Hospital, Kunming, Yunnan, China
| | - Qiao Tang
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Department of dermatology, Qionglai City Medical Center Hospital, Qionglai, Sichuan, China
| | - Yunfeng Bi
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Limei Yuan
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Binbin Yang
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xiaolan Li
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhenhui Li
- Department of Radiology, Yunnan Cancer Hospital, Kunming, Yunnan, China.
| | - Danqi Deng
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
| | - Wenting Cao
- Department of dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Zhao Q, Shen L, Lü J, Xie H, Li D, Shang Y, Huang L, Meng L, An X, Zhou J, Han J, Yu Z. A circulating miR-19b-based model in diagnosis of human breast cancer. Front Mol Biosci 2022; 9:980841. [PMID: 36188229 PMCID: PMC9523242 DOI: 10.3389/fmolb.2022.980841] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract Objective: Breast cancer (BC) is becoming the leading cause of cancer-related death in women all over the word. Identification of diagnostic biomarkers for early detection of BC is one of the most effective ways to reduce the mortality. Methods: Plasma samples from BC patients (n = 120) and normal controls (n = 50) were collected to determine the differentially expressed circulating miRNAs in BC patients. Binary logistic regression was applied to develop miRNA diagnostic models. Receiver operating characteristic (ROC) curves were applied to calculate the area under the curve (AUC). MMTV-PYMT mammary tumor mice were used to validate the expression change of those circulating miRNAs. Plasma samples from patients with other tumor types were collected to determine the specificity of the model in diagnosis of BC. Results: In the screening phase, 5 circulating miRNAs (miR-16, miR-17, miR-19b, miR-27a, and miR-106a) were identified as the most significantly upregulated miRNAs in plasma of BC patients. In consistence, the 5 miRNAs showed upregulation in the circulation of additional 80 BC patients in a tumor stage-dependent manner. Application of a tumor-burden mice model further confirmed upregulation of the 5 miRNAs in circulation. Based on these data, five models with diagnostic potential of BC were developed. Among the 5 miRNAs, miR-19b ranked at the top position with the highest specificity and the biggest contribution. In combination with miR-16 and miR-106a, a miR-19b-based 3-circulating miRNA model was selected as the best for further validation. Taken the samples together, the model showed 92% of sensitivity and 90% of specificity in diagnosis of BC. In addition, three other tumor types including prostate cancer, thyroid cancer and colorectal cancer further verified the specificity of the BC diagnostic model. Conclusion: The current study developed a miR-19b-based 3-miRNA model holding potential for diagnosis of BC using blood samples.
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Affiliation(s)
- Qian Zhao
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lei Shen
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinhui Lü
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Heying Xie
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Jinzhou Medical University, School of Basic Medical Sciences, Jinzhou, Liaoning, China
| | - Danni Li
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuanyuan Shang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liqun Huang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lingyu Meng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xuefeng An
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jieru Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Physical Examination, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Jieru Zhou, ; Jing Han, ; Zuoren Yu,
| | - Jing Han
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Jieru Zhou, ; Jing Han, ; Zuoren Yu,
| | - Zuoren Yu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Jieru Zhou, ; Jing Han, ; Zuoren Yu,
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Quadri M, Marconi A, Sandhu SK, Kiss A, Efimova T, Palazzo E. Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models. Front Med (Lausanne) 2022; 9:875517. [PMID: 35646967 PMCID: PMC9131878 DOI: 10.3389/fmed.2022.875517] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/19/2022] [Indexed: 12/07/2022] Open
Abstract
Cutaneous Squamous Cell Carcinoma (cSCC) represents the second most common type of skin cancer, which incidence is continuously increasing worldwide. Given its high frequency, cSCC represents a major public health problem. Therefore, to provide the best patients’ care, it is necessary having a detailed understanding of the molecular processes underlying cSCC development, progression, and invasion. Extensive efforts have been made in developing new models allowing to study the molecular pathogenesis of solid tumors, including cSCC tumors. Traditionally, in vitro studies were performed with cells grown in a two-dimensional context, which, however, does not represent the complexity of tumor in vivo. In the recent years, new in vitro models have been developed aiming to mimic the three-dimensionality (3D) of the tumor, allowing the evaluation of tumor cell-cell and tumor-microenvironment interaction in an in vivo-like setting. These models include spheroids, organotypic cultures, skin reconstructs and organoids. Although 3D models demonstrate high potential to enhance the overall knowledge in cancer research, they lack systemic components which may be solved only by using animal models. Zebrafish is emerging as an alternative xenotransplant model in cancer research, offering a high-throughput approach for drug screening and real-time in vivo imaging to study cell invasion. Moreover, several categories of mouse models were developed for pre-clinical purpose, including xeno- and syngeneic transplantation models, autochthonous models of chemically or UV-induced skin squamous carcinogenesis, and genetically engineered mouse models (GEMMs) of cSCC. These models have been instrumental in examining the molecular mechanisms of cSCC and drug response in an in vivo setting. The present review proposes an overview of in vitro, particularly 3D, and in vivo models and their application in cutaneous SCC research.
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Affiliation(s)
- Marika Quadri
- DermoLAB, Department of Surgical, Medical, Dental and Morphological Science, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Marconi
- DermoLAB, Department of Surgical, Medical, Dental and Morphological Science, University of Modena and Reggio Emilia, Modena, Italy
| | - Simran K Sandhu
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.,The George Washington Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.,Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Alexi Kiss
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.,The George Washington Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Tatiana Efimova
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.,The George Washington Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.,Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Elisabetta Palazzo
- DermoLAB, Department of Surgical, Medical, Dental and Morphological Science, University of Modena and Reggio Emilia, Modena, Italy
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Non-Melanoma Skin Cancer: A Genetic Update and Future Perspectives. Cancers (Basel) 2022; 14:cancers14102371. [PMID: 35625975 PMCID: PMC9139429 DOI: 10.3390/cancers14102371] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Non-melanoma skin cancer (NMSC) is the main type of cancer in the Caucasian population, and the number of cases continues to rise. Research mostly focuses on clinical characteristics analysis, but genetic features are crucial to malignancies’ establishment and advance. We aim to explore the genetic basics of skin cancer, surrounding microenvironment interactions, and regulation mechanisms to provide a broader perspective for new therapies’ development. Abstract Skin cancer is one of the main types of cancer worldwide, and non-melanoma skin cancer (NMSC) is the most frequent within this group. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common types. Multifactorial features are well-known for cancer development, and new hallmarks are gaining relevance. Genetics and epigenetic regulation play an essential role in cancer susceptibility and progression, as well as the variety of cells and molecules that interact in the tumor microenvironment. In this review, we provide an update on the genetic features of NMSC, candidate genes, and new therapies, considering diverse perspectives of skin carcinogenesis. The global health situation and the pandemic have been challenging for health care systems, especially in the diagnosis and treatment of patients with cancer. We provide innovative approaches to overcome the difficulties in the current clinical dynamics.
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MicroRNA31 and MMP-1 contribute to the differentiated pathway of invasion -with enhanced epithelial-to-mesenchymal transition- in squamous cell carcinoma of the skin. Arch Dermatol Res 2021; 314:767-775. [PMID: 34647185 DOI: 10.1007/s00403-021-02288-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 09/19/2021] [Accepted: 10/01/2021] [Indexed: 12/11/2022]
Abstract
Epithelial to mesenchymal transition (EMT) is an important mechanism of invasion in cutaneous squamous cell carcinomas (cSCCs) and has been found to be enhanced in tumors originated from actinic keratosis with transformation limited to the basal epithelial layer -differentiated pathway-, compared to cases with invasion subsequent to complete epidermal transformation -classical pathway-. Several microRNAs and proteins can contribute to EMT modulation in cSCCs. MicroRNA21 and microRNA31 are involved in posttranscriptional regulation of protein expression and could play a relevant role in EMT and cSCC progression. Throughout the EMT process upregulation of matrix metalloproteinases (MMPs) enhances invasiveness and MMP-1 and MMP-3 contribute to local invasion, angiogenesis and metastasis in cSCCs. Additionally, cSCC development is associated with PTEN loss and NF-κB, NOTCH-1 and p63 activation. The aim of this work is to identify differences in the expression of those molecules between both pathways of cSCCs development. Eight tissue microarrays from 80 consecutive cSCCs were analyzed using LNA-based miRNA in situ hybridization for miRNA21 and miRNA31 evaluation, and immunohistochemistry for MMP-1, MMP-3, PTEN, NOTCH-1, NF-κB, p63 and CD31. Significantly higher expression of miRNA31 (p < 0.0001) and MMP-1 (p = 0.0072) and angiogenesis (p = 0.0199) were found in the differentiated pathway, whereas PTEN loss (p = 0.0430) was more marked in the classical pathway. No significant differences were found for the other markers. Our findings support a contribution of miRNA31 and MMP-1 in the differentiated pathway, associated to EMT and increased microvascularization. The greater PTEN loss in the classical pathway indicate that its relevance in cSCC is not EMT-related.
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